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MOD1 > Chapter 5 > Flashcards

Chapter 5 Flashcards

1
Q

What are the 3 most important transcription factors mentioned?

A

MYC, JUN, p53

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2
Q

What is anticipation?

A

genetic disorder passed on to next generation, symptoms become apparent (and more severe) at an earlier age with each generation

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3
Q

What are the 3 symptoms of Neurofibromatosis type 1?

A

cafe au lait spots, skeletal deformities, neurofibromas

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4
Q

What are the two main patterns of disease with AD?

A
  1. regulation of complex metabolic pathways: LDL receptor in familial hypercholesterolemia (50% decrease in receptor)
  2. key structural proteins collagen and cytoskeleton elements of RBC membrane (Spectrin)
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5
Q

Caucasian male presents with malabsorption with abdominal distention, bulky foul stookls, failure to thrive. Chronic lung disease resulting from recurrent super-infections. (Mucus inspissation blocking airways, causing bronchiectasis and emphysema.) Visible secretory abnormalities of pancreas, dilated and plugged ducts.

A

Cystic fibrosis (AR): primary defect in chloride ion transport channel

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6
Q

6 month old caucasian (Scandanavian descent) presents with strong musty/mousey odor in urine and sweat. Severe mental retardation, hypopigmentation of hair and skin, eczema

A

Phenylketonuria (AR): can be treated with dietary restrictions

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7
Q

What are the 4 main categories of mendelian disorders?

A
  1. enzyme defects and their consequence
  2. defects in membrane receptors and transport systems
  3. alterations in structure, function, or quantity of non-enzyme proteins
  4. mutations resulting to unusual reactions to drugs
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8
Q

What does a deficiency of galactose-1-phosphate uridyltransferase give rise to?

A

Galactosemia

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9
Q

What does a lack of tyrosinase -> lack of melanin give rise to?

A

Albinism

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10
Q

What does an alpha-antitrypsin deficiency give rise to?

A

Emphysema: unable to inactivate neutrophil elastase in the lung

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11
Q

What does familial hypercholesterolemia lead to?

A

decrease synthesis of decrease function of LDL receptor -> defective transport of LDL into cells -> secondary increase in cholesterol synthesis

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12
Q

autosomal dominant, FBN1 chromosome 15Q21.1 (FBN2 less common), more than 75% is familial

  1. loss of structural support in microfibril rich connectiv tissue
  2. excessive activation of TGFB signaling
A

Marfan syndrome

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13
Q

Unusually tall pt, exceptionally long extremities, double jointed (can hyperextend thumb), ectopia lentis* (bilateral subluxation/dislocation of lens), dolicocephalic (long-headed with frontal bosing and prominent supraorbital ridges, pectus excavatum, mitral valve prolaspe, dilation of ascending aorta, aortic dissection* (usually cause of death)

A

Marfan syndrome

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14
Q

Defect in the synthesis/structure of fibrilar collagen, hyperextensible skin, hypermobile joints, skin is fragile and vulnerable to trauma. Minor injuries produce gaping defects (surgical repair is difficult d/t lack of normal tensile strength)
Is a basic defect in connective tissue: rupture of colon and large arteries, rupture of cornea and retinal detachment (kyphoscoliosis), diaphragmatic hernia (classic)

A

Ehlers-Danlos syndrome

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15
Q

What are clinical findings and gene defects of classic EDS (type 1/2)?

A

skin/joint hypermobility, atrophic scars, easy bruising

COL5A1, COL5A2 (AD)

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16
Q

What are clinical findings and gene defects of vascular EDS (type43)?

A

thin skin, arterial or uterine rupture, bruising, small joint hyperextensibility

COL3A1 (AD)

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17
Q

What are clinical findings and gene defects of kyphoscoliosis EDS (type 6)?

A

hypotonia, joint laxity, congenital scoliosis, ocular fragility

Lysyl hydroxylase (AR**)

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18
Q

One of most frequent mendelian disorders (1 in 500), have 2-3 fold increase in cholesterol, tendinous xanthomas (yellow cholesterol deposit along tendons).

increase in cholesterol -> premature atherosclerosis -> increase risk MI
homozygotes show 5-6 fold increase in plasma cholesterol and skin xanthomas, MI before 20

A

familial hypercholesterolemia

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19
Q

catabolism of substrate of missing enzyme remains incomplete, leading to accumulation within lysosomes (stuffed with incompletely digested macromolecules, lysosomes become large, interfere with normal cell function)

Secondary accumulation d/t impaired autophagy

A

Lysosomal storage diseases

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20
Q

Who do lysosomal storage diseases mostly affect, and what are the most common forms?

A

Storage diseases affect children (thesaurismoses) and cause hepatomegaly.

Most common are glycogen storage diseases (von Gierke disease), and sphingolipidoses (Niemann-Pick, Tay-Sachs, Gaucher diseases)

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21
Q

What results from deficiency of a transferase that converts galactose into glucose, resulting in deposition of galactose in organs (liver, spleen, kidneys, CNS, eyes)?

A

Galactosemia

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22
Q

6 month old Ashkenazi jew with mutation in alpha subunit on chromosome 15 -> severe deficiency of hexosaminidase A. Motor and mental deterioration, obtunded, flaccidity, blindness, dementia, cherry red spot in macula***, GM2 ganglioside accumulations (b/c can’t catabolize) in neurons, retina, heart, liver, spleen. fat stains oil red O and Sudan black B are positive

A

Tay-Sachs disease

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23
Q

6 month old Ashkenazi jew with visceral accumulations of sphingomyelin, progressive wasting. Missense mutation (complete lack of sphingomyelinase), death by 3yo

A

Type A Niemann-Pick disease (severe infantile form)

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24
Q

What is the most common type of Niemann-Pick disease?

A

Type C: mutation in NPC1, transport free cholesterol from lysosomes to cytoplasm. Progressive neurological damage, ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor regression

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25
Q

What are zebra bodies?

A

lysosomes with concentric lamellations (layers)

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26
Q

Is a cherry red spot seen in Niemann-Pick disease?

A

1/3-1/2 have cherry red spot on retina

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27
Q

Most common lysosomal storage disease. Accumulation of glucocerebroside in phagocytes, sometimes in CNS, damage leads to IL1, IL6 and TNF activation. Histo slide looks like crumpled tissue paper***, enlarged spleen

A

Gaucher disease

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28
Q

What are the 3 subtypes of Gaucher disease?

A

Type 1: chronic, 90% of cases, European jews, NO CNS involvement, spleen and bone issues, slight decrease in lifespan
Type 2: acute, infantile cerebral pattern, progressive CNS involvement, early death, hepatosplenomegaly, NOT JEWISH**
Type 3: intermediate, systemic involvement with progressive CNS disease that begins in adolescence/early adulthood

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29
Q

Pt presents with coarse facial features, clouding of cornea, joint stiffness, mental retardation

A

Mucopolysaccharidoses (MPS): deficiency in enzymes that degrade glycosaminoglycans, types 1-7 each with specific enzyme defect. Zebra bodies similar to Niemann-Pick

30
Q

What is the exception to AR inheritance pattern of MPS?

A

Hunter syndrome is x-linked recessive

31
Q

MPS 1-H, normal at birth, hepatosplenomegaly by 6-24 months, death by 6-10 years (cardiovascular complications- coronary arterial and valvular deposits), growth retardation, skeletal abnormalities

A

Hurler MPS

32
Q

MPS 2, x-linked, NO corneal clouding, milder clinical case

A

Hunter MPS

33
Q

Pt presents with failure to thrive, stunted growth, hepatomegaly, renomegaly, hypoglycemia d/t failure of glucose metabolsim

Enzyme def: G6P

A

Hepatorenal - von Gierke disease (type 1)

34
Q

Adult pt presents with massive cardiomegaly, muscle hypotonia, cardiorespiratory failure within 2 years, a milder form with only skeletal muscle involvement. Mild hepatomegaly and cardiomegaly

Enzyme def: lysosomal glucosidase (acid maltase)

A

Generalized glycogenosis - Pompe disease (type 2)

35
Q

What are the 3 major subgroups of glycogen storage diseases?

A
  1. hepatic forms: von Gierke (G6P def)
  2. myopathic forms: McArdle disease (muscle phosphorylase def)
  3. MISC: Pompe disease (acid maltase def or lack of branching enzyme)
36
Q

What is mosaicism?

A

mitotic errors in early development that give rise to two or more populations of cells with different chromosomal complement in same individual (mosaicism affecting sex chromosomes relatively common)

37
Q

What is a ring chromosome?

A

a chromosomal break occurs at both ends of an xsome, with fusion of damaged ends (ex: 46,XY,r14 - look for r)

38
Q

What is a Robertsonian translocation?

A

centric fusion, translocation between 2 acrocentric xsomes; typically breaks appear closer to centromeres of each xsome

NOTE: approx 3-4% of Trisomy 21 cases are caused by Robertsonian translocation (q arm of x21 is translocated onto another xsome)

39
Q

flat facial profile, oblique palpebral fissures, epicanthic folds, mental retardation, abundant neck skin, intestinal stenosis, umbilical hermia, hypotonia, gap between first and second toes

A

Trisomy 21

NOTE: 40% of cases have congenital heart disease (most commonly defects of endocardial cushion including ostium primum). By 40 years, virtually all with develop neuropathologic changes characteristic of Alzheimers disease

40
Q

What are Trisomy 21 pt’s at risk of developing?

A

10-20 fold increased risk of acute leukemia

41
Q

low set ears, short neck, overlapping fingers, congenital heart defects, renal malformations, prominant occiput, mental retardation, micrognathia, rocker-bottom feet

A

Trisomy 18: Edwards syndrome

42
Q

microcephaly, mental retardation, cleft lip and palate, micropthalmia, polydacyly, cardiac defects, renal defects, umbilical hernia, rocker-bottom feet

A

Trisomy 13: Patau syndrome

43
Q

congenital heart defects, abnormalities of the palate, facial dysmorphism, developmental delay, variable degrees of T-cell immunodeficiency, hypocalcemia

A

Chromosome 22r11.2 deletion syndrome

44
Q

thymic hypoplasia, T-cell immunodeficiency, parathyroid hypoplasia -> hypocalcemia, cardiac malformations, mild facial anomalies

A

DiGeorge syndrome

Catch 22: cardiac, abnormal facies, thymic aplasia, cleft palate, hypocalcemia/hypoPTH (xsome 22)

45
Q

facial dysmorphism (prominent nose, retrognatia), cleft palate, cardiovascular anomalies, learning disabilities

A

Velocardiofacial syndrome

46
Q

What is the Lyon hypothesis?

A
  1. only 1 xsome genetically active
  2. other X of either materal/paternal origin undergoes heteropyknosis and is rendered inactive
  3. inactivation of same X xsome persists in all cells derived from each precursor
47
Q

What is a Barr body?

A

inactive X xsome can be seen in interphase nucleus as a darkly staining small mass in contact with nuclear membrane

NOTE: normal females are mosaics with 2 populations of cells, 1 with inactivated maternal X and the other with inactivated paternal X

48
Q

47, XXY
eunuchoid body habitus with abnormally long legs, small atrophic testes and small penis, gynecomastia, lower IQ, lacking secondary male sex characteristics (deep voice, male distribution pubic hair)

A

Klinefelter syndrome

NOTE: increased risk for T2DM and metabolic syndrome, 50% mitral valve prolapse, osteoporosis and fractures d/t hormone imbalance. Important genetic cause of reduced spermatogenesis and male infertilit. 20x higher risk of breast cancer***

49
Q

45, XO
complete or patial monosomy of X xsome, characterized primarily by hypogonadism in phenotypic females

short stature, webbing of neck, cubitus valgus, CV malformations, amenorrhea, lack of secondary sex characteristics, fibrotic ovaries (streak ovaries)

  • 50% develop autoantibodies that react with thyroid gland -> hypothyroidism
  • glucose intolerance, obesity, insulin resistance
A

Turner Syndrome, 3 types:

  1. 57% missing entire X xsome (XO)
  2. common feature is to produce partial monosomy of X xsome
  3. mosaic patients have 45,X cell population plus 1 karyotypically normal type
50
Q

What is Cystic hygroma?

A

infant with edema -> swelling of the nape of the neck d/t lymph stasis

NOTE: as these infants develop, swellings subside but leave bilateral neck webbing and persistent looseness of skin on the back of the neck

51
Q

trinucleotide mutation in familial mental retardation-1 (FMR-1), mentally retarded, long face with large mandible, large everted ears, large testicles (macro-orchidism***), hyperextensible joints, high arched palate, mitral valve prolaspe

A

Fragile X syndrome: affected individuals have extremely large expansion of repeat region (200-4k repeats), 5’ region becomes abnormally methylated leading to loos of function of FMR protein

52
Q

What is inheritance pattern of fragile x syndrome?

A

x-linked, males get it from mom. males are carriers. thought that premutations are converted to mutations during oogenisis** (NOT spermigenesis)

53
Q

What is anticipation?

A

clinical features of fragile x syndrome worsen with each successive generation, as if mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons

54
Q

Progressive movement disorder and dementia, caused by degeneration of striatal neurons. jerky, hyperkinetic, dystonic movements involving all parts of body. Disease is relentlessly progressive. Prototype of polyglutamine trinucleotide repeat expansion disease

A

Huntington disease: head of caudate nucleus disappears, sulci widen, gyri narrow

55
Q

What is heteroplasmy?

A

tissues and individuals that harbor both wild type and mutant mDNA

56
Q

What is Leber hereditary optic neuropathy?

A

prototype of mDNA disorder, neurodegenerative disease that manifests as progressive bilateral loss of central vision. visual impairment is first noted between ages 15-35, eventually leads to blindness. cardiac conduction defects and minor neurologic manifestations also been observed

57
Q

Where does genetic imprinting occur?

A

In the ovum or sperm, before fertilization, and then is stably transmitted to all somatic cells through mitosis

58
Q

What is the example given of uniparental disomy?

A

Prader-Willi sydrome (paternal defect): they have two maternal copies of xsome 15

59
Q

What is the example given of defective imprinting?

A

Angelman syndome (maternal defect): maternal xsome carries the paternal imprint, hence there are no functional alleles

60
Q

Pt has mental retardation, short stature, hypotonia, profound hyphagia, obesity, small hands and feet, hypogonadism

A

Prader-Willi syndrome: in 65-75% of cases, an interstitial deletion of band q12 in the long arm of xsome 15 deletion (q11.2q13) can be detected

61
Q

Child born with a deletion in xsome 15, mentally retarded, but in addition to Prader-Willi symptoms, they present with ataxic gait, seizures, inappropriate laughter

HAPPY PUPPETS

A

Angelman syndrome

62
Q

When should you suspect a genetic syndrome?

A

the presence of one obvious malformation should not limit full evaluation, because more subtle findings will often be important in differential diagnosis.

63
Q

What does VACTERL association stand for?

A 
Vertebral
Anal anomalities
Cardiac
Tracheo-esophageal fistule
Renal anomalies
Limb anomalies
64
Q

What is Next Generation Sequencing?

A

a newer DNA sequencing technology that is capable of producing large amounts of sequence data in a massively parallel manner

NOTE: is now becoming the standard of care in lung cancers

65
Q

What is Genome-Wide Analysis?

A

Assays used to detect genetic polymorphisms, including the determination of relatedness and identity in transplants, cancer, genetics, paternity testing, and forensic medicine.

NOTE: in GWAS, large cohorts of patients with and without a disease (rather than families) are examined across the entire genome for common genetic variants or polymorphisms that are overrepresented in patients with the disease

66
Q

What is RNA analysis and what is its most important application?

A

mature mRNA contains coding sequences of all expressed genes, so RNA can substitute for DNA in a wide range of diagnostic applications.
NOTE: DNA analysis is usually preferred because it is more stable

Most important application is the detection of RNA viruses like HIV and HepC. mRNA analysis also emerging as an important tool for molecular stratification of tumors

67
Q

What are the two examples of epigenetic alterations given?

A
  1. methylation of DNA
  2. acetylation of histones

NOTE: important analysis for diagnosis of Fragile X syndrome, where hypermethylation results in FMR1 silencing. Also essential is diagnosis of Prader-Willi and Angelman syndromes

68
Q

What is FISH?

A

Fluorescence in Situ Hybridization

uses DNA probes that recognize sequences specific to particular chromosomal regions. It is used to detect numeric abnormalities of chromosomes (aneuploidy) or complex translocations that are not demonstrable by routine karyotyping

69
Q

What can be submitted for FISH testing? (4)

A
  1. formalin fixed paraffin embedded tissue
  2. prenatal sample
  3. peripheral blood
  4. cytology material (touch prep) pap smear?
70
Q

What is molecular genetic diagnosis usually used for?

A

Most often used to monitor the frequency of cancer cells bearing characteristic genetic lesions in the blood or in tissues, or the infectious load of certain viruses (HIV, EBV). It can also be used to detect somatic point mutations in oncogenes such as KRAS and BRAF, an approach that has the advantage of avoiding the need for post-PCR analysis

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